The guidance receptor neogenin promotes pulmonary inflammation during lung injury

Abstract

Lung injury is marked by a persistent self-propagating inflammation within the pulmonary tissue that is initiated by the migration of leukocytes into the alveolar space. Recent work has demonstrated that neuronal guidance proteins are involved into the orchestration of leukocyte migration. Neogenin is a crucial guidance receptor for axonal migration, yet its role during leukocyte migration and acute inflammation is to date unknown. Here, we report that neogenin influences neutrophil migration across endothelial HMEC-1 and alveolar A549 monolayers in vitro. In vivo, Neo1(-/-) mice demonstrated 59% reduced cell count, 41% reduced TNF-α, and 76% reduced IL-6 levels within the alveolar space during lung injury. In studies employing chimeric animals, the presence of Neo1(-/-) bone marrow was associated with a 42% reduction of cell count and reduced inflammatory changes within pulmonary tissue during lung injury. The functional inhibition of neogenin through antibody injection confirmed these results and the role of neogenin for the inflammatory changes within the alveolar space. Previously unappreciated, the guidance receptor neogenin has a significant effect on the orchestration of leukocyte migration and the control of acute inflammation.

RGMa Regulates Cortical Interneuron Migration and Differentiation

“…Recent reports have revealed a role for RGMa in cell migration in the context of acute inflammation where RGMa chemorepulsion of lymphocytes and neutrophils was mediated by Neo [70]. Here we demonstrate for the first time that RGMa can also promote a significant repulsive response in a population of migrating interneurons (Figs.…”

RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

“…RGMb-mediated BMP signaling was reported to inhibit IL-6 production by lung macrophages (Xia et al, 2011). Neogenin has been shown to be involved in pulmonary inflammation and acute inflammatory peritonitis (König et al, 2012; Mirakaj et al, 2012), so neogenin signaling could also be involved in the induction of respiratory tolerance. RGMb interaction with neogenin has been shown to control aggregation and migration of neogenin-positive neuroepithelial cells (Conrad et al, 2010).…”

Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo

“…For example, in an atherosclerosis model, Netrin-1 was found to retain macrophages within plaques by inhibiting macrophage emigration from the inflammatory site (5); also Netrin-1 has been found to promote chronic inflammation in adipose tissue (24). Several studies have evaluated Netrin-1 receptor biology using neogenin knockout mice which mount a reduced inflammatory peritonitis reaction (25), have less leukocyte infiltrates and reduced inflammation in models of acute lung injury (26) and ischemia reperfusion injury (27). …”